Spiro-piperidine derivatives

ABSTRACT

Present invention is concerned with novel indol-2-yl-carbonyl-spiro-piperidine derivatives as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them. The active compounds of the present invention are useful in the treatment of anxiety and depressive disorders and other diseases. The compounds of present invention have the general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1  to R 11  and X are as defined in the description.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06125645.9, filed Dec. 7, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Vasopressin is a 9 amino acid peptide mainly produced by theparaventricular nucleus of the hypothalamus. Three vasopressinreceptors, all belonging to the class I G-protein coupled receptors, areknown. The V1a receptor is expressed in the brain, liver, vascularsmooth muscle, lung, uterus and testis, the V1b or V3 receptor isexpressed in the brain and pituitary gland, the V2 receptor is expressedin the kidney where it regulates water excretion and mediates theantidiuretic effects of vasopressin.

In the periphery vasopressin acts as a neurohormone and stimulatesvasoconstriction, glycogenolysis and antidiuresis. In the brainvasopressin acts as a neuromodulator and is elevated in the amygdaladuring stress (Ebner, K., C. T. Wotjak, et al. (2002). “Forced swimmingtriggers vasopressin release within the amygdala to modulatestress-coping strategies in rats.” Eur J Neurosci 15(2): 384-8). The V1areceptor is extensively expressed in the brain and particularly inlimbic areas like the amygdala, lateral septum and hippocampus which areplaying an important role in the regulation of anxiety. Indeed V1aknock-out mouse show a reduction in anxious behavior in the plus-maze,open field and light-dark box (Bielsky, I. F., S. B. Hu, et al. (2003).“Profound Impairment in Social Recognition and Reduction in Anxiety-LikeBehavior in Vasopressin V1a Receptor Knockout Mice.”Neuropsychopharmacology). The downregulation of the V1a receptor usingantisense oligonucleotide injection in the septum also causes areduction in anxious behavior (Landgraf, R., R. Gerstberger, et al.(1995). “V1 vasopressin receptor antisense oligodeoxynucleotide intoseptum reduces vasopressin binding, social discrimination abilities, andanxiety-related behavior in rats.” Regul Pept 59(2): 229-39).

The V1a receptor is also mediating the cardiovascular effects ofvasopressin in the brain by centrally regulating blood pressure andheart rate in the solitary tract nucleus (Michelini, L. C. and M. Morris(1999). “Endogenous vasopressin modulates the cardiovascular responsesto exercise.” Ann NY Acad Sci 897: 198-211). In the periphery it inducesthe contraction of vascular smooth muscles and chronic inhibition of theV1a receptor improves hemodynamic parameters in myocardial infarctedrats (Van Kerckhoven, R., I. Lankhuizen, et al. (2002). “Chronicvasopressin V(1A) but not V(2) receptor antagonism prevents heartfailure in chronically infarcted rats.” Eur J Pharmacol 449(1-2):135-41)

SUMMARY OF THE INVENTION

The present invention provides novelindol-2-yl-carbonyl-spiro-piperidine derivatives as V1a receptorantagonists, their manufacture, pharmaceutical compositions containingthem and their use for the treatment of anxiety and depressive disordersand other diseases.

In particular, the present invention provides compounds of formula (I)

wherein

-   X is O or CH₂;-   R¹ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH. or    -   —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b);-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano, or    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;-   R³ is hydrogen,    -   halo, or    -   C₁₋₆-alkyl;-   R⁴ is hydrogen,    -   halo,    -   C₁₋₆-alkyl,    -   halo-C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy, or    -   —O—C₂₋₁₀-alkenyl;-   R⁵ is hydrogen,    -   halo,    -   C₁₋₆-alkyl, or    -   C₁₋₆-alkoxy;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j),    -   —O-benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   —(C₁₋₃-alkylene)-R^(m),        -   wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl,        -   4- to 6-membered heterocycloalkyl or 3 to 6-membered            cycloalkyl, each optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano;-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein —R⁵—R⁶ is —O—(CH₂)_(n)—C(O)—,    -   —C(O)—(CH₂)_(n)—O—, or    -   —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁷ is hydrogen or C₁₋₆-alkyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, halo,    C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or halo-C₁₋₆alkoxy;-   R^(a), R^(b), R^(i) and R^(j) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-NR^(k)R^(l);        -   wherein R^(k) and R^(l) are each independently hydrogen or            C₁₋₆-alkyl,    -   or R^(a) and R^(b), or R^(i) and R^(j) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;-   R^(c), R^(d), R^(g) and R^(h) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —C(O)R^(e), or —S(O)₂R^(e),        -   wherein R^(e) is selected from            -   hydrogen,            -   C₁₋₆-alkyl, and            -   phenyl, optionally substituted by one or more halo,                -   halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                -   halo-C₁₋₆-alkoxy, nitro, or cyano, or    -   R^(c) and R^(d), or R^(g) and R^(h) together with the nitrogen        to which they are bound form a five or six membered heterocycle        comprising one or two heteroatoms selected from the group of        nitrogen, oxygen and sulfur, or        -   R^(c) and R^(d), or R^(g) and R^(h) together with the            nitrogen to which they are bound form isoindole-1,3-dione;-   R^(f) is selected from    -   hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy; and    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;        or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to a person skilled in the art. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below, by methods described in references cited in thetext or in the examples, or by methods known in the art.

The compounds of formula (I) possess pharmaceutical activity, inparticular they are modulators of V1a receptor activity. Moreparticular, the compounds are antagonists of the V1a receptor.

The present invention provides compounds which act as V1a receptormodulators, and in particular as V1a receptor antagonists. Suchantagonists are useful as therapeutics in the conditions ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders. The preferredindications with regard to the present invention are the treatment ofanxiety and depressive disorders.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

In the present description, the term “alkyl,” alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated hydrocarbon radical. The term “C₁₋₆-alkyl” denotes a saturatedstraight- or branched-chain hydrocarbon group containing from 1 to 6carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, the isomeric pentyls and the like. A preferredsub-group of C₁₋₆-alkyl is C₁₋₄-alkyl, i.e. with 1-4 carbon atoms.

In the present invention, the term “alkylene” refers to a linear orbranched saturated divalent hydrocarbon radical. In particular,“C₁₋₆-alkylene” means a linear saturated divalent hydrocarbon radical ofone to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g. methylene, ethylene,2,2-dimethylethylene, n-propylene, 2-methylpropylene, and the like.

In the present description, the terms “alkoxy” and “C₁₋₆-alkoxy” referto the group R′—O—, wherein R′ is C₁₋₆-alkyl as defined above. Examplesof alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy and the like. A preferred sub-group ofC₁₋₆-alkoxy, and still more preferred alkoxy groups are methoxy and/orethoxy.

In the present description, the terms “thioalkyl” and “C₁₋₆-thioalkyl”refer to the group R′—S—, wherein R′ is C₁₋₆-alkyl as defined above.

The terms “C₁₋₆-hydroxyalkyl” and “C₁₋₆-alkyl substituted by OH” denotea C₁₋₆-alkyl group as defined above wherein at least one of the hydrogenatoms of the alkyl group is replaced by a hydroxyl group.

The terms “C₁₋₆-cyanoalkyl” and “C₁₋₆-alkyl substituted by CN” denote aC₁₋₆-alkyl group as defined above wherein at least one of the hydrogenatoms of the alkyl group is replaced by a CN group.

The terms “halo” or “halogen” refer to fluorine (F), chlorine (Cl),bromine (Br) and iodine (I) with fluorine, chlorine and bromine beingpreferred.

The term “halo-C₁₋₆-alkyl” denotes a C₁₋₆-alkyl group as defined abovewherein at least one of the hydrogen atoms of the alkyl group isreplaced by a halogen atom, preferably fluoro or chloro, most preferablyfluoro. Examples of halo-C₁₋₆-alkyl include but are not limited tomethyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s) aswell as those groups specifically illustrated by the examples hereinbelow. Among the preferred halo-C₁₋₆-alkyl groups are difluoro- ortrifluoro-methyl or -ethyl.

The term “halo-C₁₋₆-alkoxy” denotes a C₁₋₆-alkoxy group as defined abovewherein at least one of the hydrogen atoms of the alkyl group isreplaced by a halogen atom, preferably fluoro or chloro, most preferablyfluoro. Among the preferred halogenated alkoxy groups are difluoro- ortrifluoro-methoxy or -ethoxy.

The term “C₂₋₁₂-alkenyl”, alone or in combination, denotes astraight-chain or branched hydrocarbon residue of 2 to 12 carbon atomscomprising at least one double bond. A preferred sub-group ofC₂₋₁₂-alkenyl is C₂₋₆-alkyenyl. Examples of the preferred alkenyl groupsare ethenyl, propen-1-yl, propen-2-yl (allyl), buten-1-yl, buten-2-yl,buten-3-yl, penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl,hexen-1-yl, hexen-2-yl, hexen-3-yl, hexen-4-yl and hexen-5-yl, as wellas those specifically illustrated by the examples herein below.

The term “5 or 6 membered heteroaryl” means an aromatic ring of 5 or 6ring atoms as ring members containing one, two, or three ringheteroatoms selected from N, O, or S, the rest being carbon atoms. 5 or6 membered heteroaryl can optionally be substituted with one, two, threeor four substituents, wherein each substituent may independently beselected from the group consisting of hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-thioalkyl, halo, cyano, nitro, halo-C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl,C₁₋₆-alkoxycarbonyl, amino, C₁₋₆-alkylamino, di(C₁₋₆)alkylamino,aminocarbonyl, or carbonylamino, unless otherwise specificallyindicated. Preferred substituents are halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, optionally substituted oxazolyl, optionally substitutedthiazolyl, optionally substituted pyrazinyl, optionally substitutedpyrrolyl, optionally substituted pyrazinyl, optionally substitutedpyridinyl, optionally substituted pyrimidinyl, optionally substitutedfuranyl, and those which are specifically exemplified herein.

The term “heterocycloalkyl” means a monovalent saturated moiety,consisting of one ring of 3 to 7, preferably from 4 to 6 atoms as ringmembers, including one, two, or three heteroatoms chosen from nitrogen,oxygen or sulfur, the rest being carbon atoms. 3 to 7 memberedheterocycloalkyl can optionally be substituted with one, two, three orfour substituents, wherein each substituent is independently hydroxy,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-thioalkyl, halo, cyano, nitro,halo-C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-alkoxycarbonyl, amino,C₁₋₆-alkylamino, di(C₁₋₆)alkylamino, aminocarbonyl, or carbonylamino,unless otherwise specifically indicated.

Preferred substituents are halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano. Examples of heterocyclicmoieties include, but are not limited to, optionally substitutedtetrahydro-furanyl, optionally substituted piperidinyl, optionallysubstituted pyrrolidinyl, optionally substituted morpholinyl, optionallysubstituted piperazinyl, and the like or those which are specificallyexemplified herein.

The term “heterocycle” in the definition “R^(a) and R^(b), R^(c) andR^(d), R^(g) and R^(h), R^(i) and R^(j), together with the nitrogen towhich they are bound form a five- or six-membered heterocycle comprisingone or two heteroatoms selected from the group of nitrogen, oxygen andsulfur” means either heterocycloalkyl or heteroaryl in the above-givensense, which may optionally be substituted as described above.Preferably, the “heterocycle” may optionally be substituted with one,two or three substituents selected from halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano. Preferredheterocycles are piperazine, N-methylpiperazine, morpholin, piperidineand pyrrolidine.

The term “one or more” substituents preferably means one, two or threesubstituents per ring.

The term “3- to 6-membered cycloalkyl” denotes a saturated or partiallysaturated ring containing from 3 to 6 carbon atoms, for examplecyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salt” embraces saltswith inorganic and organic acids, such as hydrochloric acid, nitricacid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaricacid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

In detail, the present invention relates to compounds of the generalformula (I)

wherein

-   X is O or CH₂;-   R¹ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH. or    -   —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b);-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano, or    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;-   R³ is hydrogen,    -   halo, or    -   C₁₋₆-alkyl;-   R⁴ is hydrogen,    -   halo,    -   C₁₋₆-alkyl,    -   halo-C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy, or    -   —O—C₂₋₁₀-alkenyl;-   R⁵ is hydrogen,    -   halo,    -   C₁₋₆-alkyl, or    -   C₁₋₆-alkoxy;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j),    -   —O-benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   —(C₁₋₃-alkylene)-R^(m),        -   wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl,        -   4- to 6-membered heterocycloalkyl or 3 to 6-membered            cycloalkyl, each optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano;-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein —R⁵—R⁶ is —O—(CH₂)_(n)—C(O)—,    -   —C(O)—(CH₂)_(n)—O—, or    -   —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁷ is hydrogen or C₁₋₆-alkyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, halo,    C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or halo-C₁₋₆alkoxy;-   R^(a), R^(b), R^(i) and R^(j) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-NR^(k)R^(l);        -   wherein R^(k) and R^(l) are each independently hydrogen or            C₁₋₆-alkyl,    -   or R^(a) and R^(b), or R^(i) and R^(j) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;-   R^(c), R^(d), R^(g) and R^(h) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —C(O)R^(e), or —S(O)₂R^(e),        -   wherein R^(e) is selected from            -   hydrogen,            -   C₁₋₆-alkyl, and            -   phenyl, optionally substituted by one or more halo,                -   halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                -   halo-C₁₋₆-alkoxy, nitro, or cyano, or    -   R^(c) and R^(d), or R^(g) and R^(h) together with the nitrogen        to which they are bound form a five or six membered heterocycle        comprising one or two heteroatoms selected from the group of        nitrogen, oxygen or sulfur, or        -   R^(c) and R^(d), or R^(g) and R^(h) together with the            nitrogen to which they are bound form isoindole-1,3-dione;-   R^(f) is selected from    -   hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy; and    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;        or a pharmaceutically acceptable salt thereof.

In certain embodiments of the invention, R^(a) and R^(b), R^(c) andR^(d), R^(i) and R^(j), or R^(g) and R^(h) together with the nitrogen towhich they are bound may form piperazine, 4-(C₁₋₆-alkyl)-piperazine,4-methylpiperazine, morpholine, piperidine or pyrrolidine.

In certain embodiments of the invention, wherein R^(m) is a 5- to6-membered heteroaryl, the preferred heteroaryl is selected from thegroup consisting of pyridine, pyrimidine, pyrazine, pyridazine,imidazole, pyrazole, oxazole, and isoxazole.

In embodiments of the invention, wherein R^(m) is a 4- to 6-memberedheterocycloalkyl, the preferred heterocycloalkyl is selected from thegroup consisting of pyrrolidine, oxethane, tetrahydropyrane, piperidine,morpholine, and piperazine.

In certain embodiments of the invention, R¹ is hydrogen or C₁₋₆-alkyl,optionally substituted by CN or OH.

In certain embodiments of the invention,

-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),        -   wherein R^(c) and R^(d) are each independently            -   hydrogen,            -   —C(O)R^(e), or —S(O)₂R^(e),                -   wherein R^(e) is selected from                -    hydrogen,                -    C₁₋₆-alkyl, and                -    phenyl, optionally substituted by one or more halo,                    halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                    halo-C₁₋₆-alkoxy, nitro, or cyano, or            -   R^(c) and R^(d) together with the nitrogen to which they                are bound form isoindole-1,3-dione;        -   -(C₁₋₆-alkylene)-C(O)R^(f),            -   wherein R^(f) is selected from                -   hydrogen,                -   C₁₋₆-alkyl,                -   C₁₋₆-alkoxy, and                -   phenyl, optionally substituted by one or more halo,                    halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                    halo-C₁₋₆-alkoxy, nitro, or cyano;        -   benzyl, optionally substituted by halo, halo-C₁₋₆-alkyl,            C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano,            or        -   phenyl, optionally substituted by halo, halo-C₁₋₆-alkyl,            C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano.

In certain embodiments of the invention, R² is hydrogen or C₁₋₆-alkyl.

In certain embodiments of the invention, R³ is hydrogen.

In certain embodiments of the invention, R⁴ is hydrogen, halo,C₁₋₆-alkyl, or C₁₋₆-alkoxy.

In certain embodiments of the invention,

-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),        -   wherein R^(g) and R^(h) are each independently selected from            hydrogen, and C₁₋₆-alkyl; or wherein        -   R^(g) and R^(h) together with the nitrogen to which they are            bound form a five or six membered heterocycle comprising one            or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur,    -   -(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j),        -   wherein R^(i) and R^(j) are each independently            -   hydrogen,            -   C₁₋₆-alkyl,            -   —(C₁₋₆-alkylene)-NR^(k)R^(l),                -   wherein R^(k) and R^(l) are each independently                    hydrogen or C₁₋₆-alkyl,        -   or R^(i) and R^(j) together with the nitrogen to which they            are bound form a five or six membered heterocycle comprising            one or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur,    -   —O-benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f),        -   R^(f) is selected from            -   hydrogen,            -   C₁₋₆-alkyl,            -   C₁₋₆-alkoxy, or            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano,    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   -(C₁₋₃-alkylene)-R^(m),        -   wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4-            to 6-membered heterocycloalkyl or 3 to 6-membered            cycloalkyl,            -   each optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano.

In certain embodiments of the invention,

-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),        -   wherein R^(g and R) ^(h) are each independently selected            from hydrogen, and C₁₋₆-alkyl; or wherein        -   R^(g) and R^(h) together with the nitrogen to which they are            bound form a five or six membered heterocycle comprising one            or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur,    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j),        -   wherein R^(i) and R^(j) are each independently            -   hydrogen,            -   C₁₋₆-alkyl,            -   —(C₁₋₆-alkylene)-NR^(k)R^(l),                -   wherein R^(k) and R^(l) are each independently                    hydrogen or C₁₋₆-alkyl,        -   or R^(i) and R^(j) together with the nitrogen to which they            are bound form a five or six membered heterocycle comprising            one or two heteroatoms selected from the group of nitrogen            and oxygen.

In certain embodiments of the invention, R⁶ is hydrogen or C₁₋₆-alkyl.

In certain embodiments of the invention, R⁷ is hydrogen.

In certain embodiments all R⁸ to R¹¹ are hydrogen.

In certain embodiments, R⁸ to R¹¹ are independently hydrogen or halo.

In certain embodiments, R⁹ is fluoro, and R⁸, R¹⁰ and R¹¹ are hydrogen.

In certain embodiments, R⁸, R⁹ and R¹¹ are hydrogen and R¹⁰ is bromo.

In certain embodiments, R⁸ to R¹¹ are independently hydrogen or methyl.

In certain embodiments, R⁸ to R¹⁰ are hydrogen and R¹¹ is methyl.

In certain embodiments of the invention, X is O, i.e. compounds offormula (Ia)

wherein R¹ to R¹¹ are as defined herein above.

In certain embodiments of the invention, X is CH₂, i.e. compounds offormula (Ib)

wherein R¹ to R¹¹ are as defined herein above.

In certain embodiments of the invention, R¹ to R⁶ are not all hydrogen.

In certain embodiments of the invention, R¹ to R¹¹ are not all hydrogen.

The invention further encompasses an embodiment with the compound offormula (I), wherein

-   X is O or CH₂;-   R¹ is hydrogen;    -   C₁₋₆-alkyl, optionally substituted by CN or OH;    -   -(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b),        -   wherein R^(a) and R^(b) are each independently hydrogen or            C₁₋₆-alkyl,-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),        -   wherein R^(c) and R^(d) are each independently            -   hydrogen,            -   —C(O)R^(e), or —S(O)₂R^(e),                -   wherein R^(e) is selected from                -    hydrogen,                -    C₁₋₆-alkyl, and                -    phenyl, optionally substituted by one or more halo,                    halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                    halo-C₁₋₆-alkoxy, nitro, or cyano, or        -   R^(c) and R^(d) together with the nitrogen to which they are            bound form isoindole-1,3-dione,    -   —(C₁₋₆-alkylene)-C(O)R^(f),        -   wherein R^(f) is selected from            -   hydrogen,            -   C₁₋₆-alkyl,            -   C₁₋₆-alkoxy, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano,    -   benzyl, optionally substituted by halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano or    -   phenyl, optionally substituted by halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano;-   R³ is hydrogen,    -   halo, or    -   C₁₋₆-alkyl;-   R⁴ is hydrogen,    -   halo,    -   C₁₋₆-alkyl,    -   halo-C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy, or    -   —O—C₂₋₁₀-alkenyl;-   R⁵ is hydrogen,    -   halo,    -   C₁₋₆-alkyl, or    -   C₁₋₆-alkoxy;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),        -   wherein R^(g) and R^(h) are each independently selected from            hydrogen, and C₁₋₆-alkyl, or wherein        -   R^(g) and R^(h) together with the nitrogen to which they are            bound form a five or six membered heterocycle comprising one            or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur,    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j),        -   wherein R^(i) and R^(j) are each independently            -   hydrogen,            -   C₁₋₆-alkyl,            -   —(C₁₋₆-alkylene)-NR^(k)R^(l),                -   wherein R^(k) and R^(l) are each independently                    hydrogen or C₁₋₆-alkyl;        -   or R^(i) and R^(j) together with the nitrogen to which they            are bound form a five or six membered heterocycle comprising            one or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur,    -   —O-benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f); wherein        -   R^(f) is selected from            -   hydrogen,            -   C₁₋₆-alkyl,            -   C₁₋₆-alkoxy, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano,        -   phenyl, optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano,        -   —(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to            6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or            3 to 6-membered cycloalkyl, each optionally substituted by            one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,            halo-C₁₋₆-alkoxy, nitro, or cyano;-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein —R⁵—R⁶ is —O—(CH₂)_(n)—C(O)—,    -   —C(O)—(CH₂)_(n)—O—, or    -   —O—(CH₂)_(n)—O— wherein n is 1 or 2,-   R⁷ is hydrogen or C₁₋₆-alkyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, halo,    C₁₋₆-alkyl or halo-C₁₋₆-alkyl.

The invention further encompasses an embodiment with the compound offormula (I), wherein

-   X is O or CH₂;-   R¹ is hydrogen, or C₁₋₆-alkyl, optionally substituted by CN or OH;-   R² is hydrogen or C₁₋₆-alkyl;-   R³ is hydrogen;-   R⁴ is hydrogen,    -   halo,    -   C₁₋₆-alkyl, or    -   C₁₋₆-alkoxy;-   R⁵ is hydrogen or halo;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2,-   R⁶ is hydrogen or C₁₋₆-alkyl, optionally substituted by CN or OH;-   R⁷ is hydrogen or C₁₋₆-alkyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen or halo.

The invention further encompasses an embodiment with the compound offormula (Ia), wherein

-   X is O;-   R¹ is hydrogen, or C₁₋₆-alkyl, optionally substituted by CN or OH;-   R² is hydrogen or C₁₋₆-alkyl;-   R³ is hydrogen;-   R⁴ is hydrogen, halo, or C₁₋₆-alkyl;-   R⁵ is hydrogen or halo;-   R⁶ is hydrogen or C₁₋₆-alkyl, optionally substituted by CN or OH;-   R⁷ is hydrogen;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen.

The invention further encompasses an embodiment with the compound offormula (Ib), wherein

-   X is CH₂;-   R¹ is hydrogen, or C₁₋₆-alkyl, optionally substituted by CN or OH;-   R² is hydrogen or C₁₋₆-alkyl;-   R³ is hydrogen;-   R⁴ is hydrogen, halo, or C₁₋₆-alkoxy;-   R⁵ is hydrogen;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2,-   R⁶ is hydrogen;-   R⁷ is hydrogen;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen or halo.

Preferred compounds of the invention are those shown in the examples.

More preferred compounds of formula Ia:

-   1′-[(5-chloro-1-methyl-1H-indol-2-yl)carbonyl]spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one,-   {2-[(2-oxo-1,2-dihydro-1′H-spiro[3,1-benzoxazine-4,4′-piperidin]-1′-yl)carbonyl]-1H-indol-1-yl}acetonitrile,    and-   {5-chloro-2-[(2-oxo-1,2-dihydro-1′H-spiro[3,1-benzoxazine-4,4′-piperidin]-1′-yl)carbonyl]-1H-indol-1-yl}acetonitrile.

More preferred compound of formula Ib:

-   {2-[(6′-bromo-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinolin]-1-yl)carbonyl]-5-chloro-1H-indol-1-yl}acetonitrile.

The invention also encompasses the compounds of formula (I) for a use inthe prevention or treatment of dysmenorrhea, hypertension, chronic heartfailure, inappropriate secretion of vasopressin, liver cirrhosis,nephrotic syndrome, obsessive compulsive disorder, anxiety anddepressive disorders.

The invention also encompasses a pharmaceutical composition comprising acompound of formula (I) which pharmaceutical composition is usefulagainst dysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders. Thepharmaceutical composition may further comprise at least onepharmaceutically acceptable excipient.

The invention further encompasses the use of a compound of formula (I)for the preparation of a medicament which is useful againstdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders.

In a certain embodiment, the compound of the invention can bemanufactured according to a process comprising reacting a compound offormula (II):

with an amine of formula 1

wherein R¹ to R¹¹ and X are as defined above.

In a certain embodiment, the compound of the invention can bemanufactured according to a process comprising reacting a compound offormula (I-1):

with an electrophile of formula R¹-hal, to give a compound of generalformula (I) as defined herein above.

The synthesis of compounds of general formula (I) will be described inmore detail below and in the examples. The compounds of formula I may beprepared in accordance with the process variants as described above andwith the following schemes A-C. The starting materials described in theExample section are either commercially available or are otherwise knownor derived from the chemical literature, for instance as cited below, ormay be prepared as described in the Examples section.

where in A is:

wherein X is O or CH₃

Compounds of formula (I) can be prepared via an amide coupling betweenan indole 2-carboxylic acid (II) and a compound of formula (A-H),wherein A is defined as hereinabove. The usual reagents and protocolsknown in the art can be used to effect the amide coupling. Indole2-carboxylic acids (II) are either commercially available or readilyprepared using procedures described hereinafter. The compounds offormula (A-H) are either commercially available or prepared usingmethods known in the art starting from commercially available materials.General scheme A is hereinafter further illustrated with generalprocedure I.

Compounds of formula (I-2) (compounds of formula (I) wherein R¹ isdifferent from H), can be prepared by alkylation of the indolederivative of formula (I-1), with an electrophile of formula R¹-hal(commercially available, wherein hal is halo, preferably Cl or Br) usingstandard procedures. Derivatives (I-1) are prepared using the amidecoupling as described in the general scheme A.

Substituted indole 2-carboxylic acids can be prepared according to thegeneral scheme C. Indoles V are obtained by a Fischer indole synthesisfrom an aryl hydrazine III and a α-ketoester IV. Saponification gives anacid of formula II-a. Alternatively, Boc protection of the indolenitrogen gives VI. Selective bromination of the methyl group in the7-position of the indole using NBS affords VII. Subsequent nucleophilicsubstitution of 7-bromomethyl indole intermediate VII with NaCN or asecondary amine yields intermediates VIII and IX, respectively. AfterN-deprotection and saponification of the ester moiety, the correspondingcarboxylics acids II-b and II-c are obtained.

Abbreviations used:

NBS=N-Bromosuccinimide

Boc=tert-buthoxycarbonylEDC=N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochlorideHOBt=1-hydroxybenzotriazole

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxideDMAP=4-dimethylaminopyridineTFA=trifluoroacetic acid

V1a Activity Material & Method:

The human V1a receptor was cloned by RT-PCR from total human liver RNA.The coding sequence was subcloned in an expression vector aftersequencing to confirm the identity of the amplified sequence. Todemonstrate the affinity of the compounds from the present invention tothe human V1a receptor binding studies were performed. Cell membraneswere prepared from HEK293 cells transiently transfected with theexpression vector and grown in 20 liter fermenters with the followingprotocol.

50 g of cells were resuspended in 30 ml freshly prepared ice cold Lysisbuffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2 adjusted to pH=7.4+completecocktail of protease inhibitor (Roche Diagnostics)). Homogenized withPolytron for 1 min and sonicated on ice for 2×2 minutes at 80% intensity(Vibracell sonicator). The preparation was centrifuged 20 min at 500 gat 4° C., the pellet was discarded and the supernatant centrifuged 1hour at 43'000 g at 4° C. (19'000 rpm). The pellet was resuspended in12.5 ml Lysis buffer+12.5 ml Sucrose 20% and homogenized using aPolytron for 1-2 min. The protein concentration was determined by theBradford method and aliquots were stored at −80° C. until use. Forbinding studies 60 mg Yttrium silicate SPA beads (Amersham) were mixedwith an aliquot of membrane in binding buffer (50 mM Tris, 120 mM NaCl,5 mM KCl, 2 mM CaCl2, 10 mM MgCl2) for 15 minutes with mixing. 50 ul ofbead/membrane mixture was then added to each well of a 96 well plate,followed by 50 ul of 4 nM 3H-Vasopressin (American RadiolabeledChemicals). For total binding measurement 100 ul of binding buffer wereadded to the respective wells, for non-specific binding 100 ul of 8.4 mMcold vasopressin and for compound testing 100 ul of a serial dilution ofeach compound in 2% DMSO. The plate was incubated 1 h at roomtemperature, centrifuged 1 min at 1000 g and counted on a PackardTop-Count. Non-specific binding counts were subtracted from each welland data was normalized to the maximum specific binding set at 100%. Tocalculate an IC 50 the curve was fitted using a non-linear regressionmodel (XLfit) and the Ki was calculated using the Cheng-Prussoffequation.

Ex. pKi (hV1a) 7 7.325 14 7.525 15 7.22 16 7.975

The present invention also provides pharmaceutical compositionscontaining compounds of formula I and/or their pharmaceuticallyacceptable acid addition salts. Such compositions can be in the form oftablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc canbe used as such excipients e.g. for tablets, dragées and hard gelatinecapsules.

Suitable excipients for soft gelatine capsules are e.g. vegetable oils,waxes, fats, semi-solid and liquid polyols etc. Suitable excipients forthe manufacture of solutions and syrups are e.g. water, polyols,saccharose, invert sugar, glucose etc. Suitable excipients for injectionsolutions are e.g. water, alcohols, polyols, glycerol, vegetable oilsetc. Suitable excipients for suppositories are e.g. natural or hardenedoils, waxes, fats, semi-liquid or liquid polyols etc.

Moreover, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 10 to 1000 mg per person of acompound of general formula (I) should be appropriate, although theabove upper limit can also be exceeded when necessary.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

EXAMPLE A

Tablets of the following composition can be manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn starch 15 Macrocrystallinecellulose 34 Magnesium stearate 1 Tablet weight 100

EXAMPLE B

Capsules of the following composition can be manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight 200

The active substance, lactose and corn starch can be firstly mixed in amixer and then in a comminuting machine. The mixture can be returned tothe mixer, the talc can be added thereto and mixed thoroughly. Themixture can be filled by machine into hard gelatine capsules.

EXAMPLE C

Suppositories of the following composition can be manufactured:

mg/supp. Active substance 15 Suppository mass 1285 Total 1300

The suppository mass can be melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered activesubstance can be added thereto and stirred until it has dispersedcompletely. The mixture can be poured into suppository moulds ofsuitable size, left to cool; the suppositories then can be removed fromthe moulds and packed individually in wax paper or metal foil.

In the following, the synthesis of compounds of formula (I) is furtherexemplified:

The compounds of formula I may be prepared in accordance with theprocess variants as described above. The starting materials described inthe Example section are either commercially available or are otherwiseknown or derived from the chemical literature, for instance as citedbelow, or may be prepared as described in the Examples section.

EXAMPLES General Procedure I Amide Coupling

To a 0.1 M stirred solution of an indole-2-carboxylic acid derivative oftype (II) in CH₂Cl₂ are added EDC (1.3 eq), HOBt (1.3 eq), Et₃N (1.3 eq)and the amine derivative (A-H, as defined above, 1 eq). The mixture isstirred overnight at room temperature and then poured onto water andextracted with CH₂Cl₂. The combined organic phases are dried over Na₂SO₄and concentrated in vacuo. Flash chromatography or preparative HPLCaffords a compound of formula (I).

General Procedure II Alkylation

To a 0.1 M stirred solution of a derivative of general formula (I-1) inDMF is added NaH (60% in oil, 2.1 eq.). After stirring the mixture atroom temperature for 30 min. the electrophilic reactant R¹-hal (1.1 eq.)is added. The mixture is stirred an additional 14 hours at 60° C. andthen poured onto water and extracted with ethyl acetate. The combinedorganic phases are dried over Na₂SO₄ and concentrated in vacuo.Purification by preparative HPLC affords the corresponding derivativesof general formula (I-2).

Example 16′-Bromo-1-[(5-methoxy-3-methyl-1H-indol-2-yl)carbonyl]-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one

Amide coupling according to general procedure I:

-   -   Amine: 6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        (prepared herein),    -   Acid: 5-Methoxy-3-methyl-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 482.4 (M+H⁺).

6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one (Scheme 1)

1′-(tert-Butyloxycarbonyl)spiro(indene-1,4′-piperidine) 3

To a solution of indene 1 (34.6 g, 298 mmol) in dry THF (40 mL)maintained under a nitrogen blanket was added lithiumbis(trimethylsilyl) amide (596 mL of a 1.0 M solution in THF; 596 mmol)over 30 min. The mixture was stirred in the cold for 30 min and thentransferred by a cannula to a solution ofN,N-bis(2-chloroethyl)-tert-butyl carbamate 2 (68 g, 281 mmol) in dryTHF (40 mL), and stirred in an ice bath. The mixture was stirred for 2hours in the cold and for 30 min at ambient temperature under nitrogenand then evaporated in vacuo to a foam. Methylene chloride was added andthe resulting reaction mixture was chromatographed on silica (1:20 ethylacetate-hexane). The product fractions were evaporated to dryness invacuo to give (49 g, 57%) of1′-(tert-butyloxycarbonyl)spiro(indene-1,4′-piperidine) 3 as a whitesolid, mp 128° C. IR (KBr) 3435, 2964, 2856, 1679, 1427, 1165 cm-1; 1HNMR (CDCl3, 400 MHz) δ 1.26 (br d, J=13.4 Hz, 2H), 1.43 (s, 9H), 1.93(dt, J=12.9, 4.5 Hz, 2H), 3.04 (dt, J=13.0, 2.7 Hz, 2H), 4.11 (br d,J=13.5 Hz, 2H), 6.71 (d, J=5.7 Hz, 1H), 6.77 (d, J=5.7 Hz, 1H),7.11-7.19 (m, 2H), 7.23-7.26 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 28.47,33.39, 42.48, 52.03, 79.56, 121.45, 121.65, 125.30, 126.98, 130.25,140.32, 142.73, 151.65, 155.01; GC MS (EI) m/z 285.

1′-(tert-Butyloxycarbonyl)spiro(indan-1-ol,4′-piperidine) 5

To a stirring solution of 3 (20 g, 70.2 mmol) in dry methylene chloride(450 mL) was passed gaseous HBr for 12 hours. The reaction mixture wascarefully neutralized with saturated sodium bicarbonate solution (150mL). The aqueous part was separated out and the organic part backextracted with saturated sodium bicarbonate (2×50 mL). To the aqueousextract and the combined washings was added 14.7 g of solid sodiumbicarbonate, 400 mL of methylene chloride followed by 15.4 g (70.2 mmol)of di-tert-butyl pyrocarbonate. The reaction mixture was stirred atambient temperature for 3 hours. The organic layer was separated out andthe aqueous part was washed successively with methylene chloride (3×50mL), dried and concentrated in vacuo to provide a foaming liquid whichwas chromatographed on silica (3:7 ethyl acetate-hexane followed by 1:1ethyl acetate-hexane) to provide1′-(tert-butyloxycarbonyl)spiro(indan-1-ol, 4′-piperidine) 5 (21 g, 99%)as a viscous liquid. IR (film) 3401, 2925, 2347, 1691, 1669, 1425, 1365,1166 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.37 (dd, J=13.4, 2.0 Hz, 1H), 1.49(s, 9H), 1.62 (dd, J=13.2, 1.9 Hz, 1H), 1.73 (dt, J=13.0, 4.4 Hz, 1H),1.87-1.96 (m, 2H), 2.49 (dd, J=13.4, 7.1 Hz, 1H), 2.62 (br s, 1H), 2.92(tt, J=11.7, 2.9 Hz, 2H), 4.09 (d, J=11 Hz, 2H), 5.25 (t, J=12.2 Hz,1H), 7.18 (d, J=7.4 Hz, 1H), 7.25-7.33 (m, 2H), 7.41 (d, J=7.09 Hz, 1H);13C NMR (CDCl3, 100 MHz) δ 28.39, 37.04, 38.04, 41.21, 41.37, 44.70,44.94, 73.98, 79.52, 122.59, 124.43, 127.48, 128.64, 143.96, 150.10,154.90; MS (EI) m/z 303.

1′-(tert-Butyloxycarbonyl)-spiro-(indan-1-one, 4′-piperidine) 6

A stirring solution of 5 (20 g, 66 mmol) in ethyl acetate (300 mL) wastreated with o-iodoxybenzoic acid (IBX) (37 g, 132 mmol) and was heatedat 80° C. for 12 hours. The reaction mixture was brought to roomtemperature and then filtered under pump. The residue was thoroughlywashed with ethylacetate (3×100 mL). The filtrate with the combinedwashings were concentrated under vacuo to provide a solid residue whichwas chromatographed over silica (1:10 ethyl acetate-hexane followed by1:3 ethyl acetate-hexane) to provide1′-(tert-butyloxycarbonyl)-spiro-(indanl-one,4′-piperidine) 6 (19.5 g,98%) as a white solid, mp 121° C. IR (KBr) 3388, 2980, 2917, 2847, 1704,1688, 1603, 1418, 1364, 1278, 1160 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.46(s, 9H), 1.49 (m, 2H), 1.95 (dt, J=13.2, 4.6 Hz, 2H), 2.60 (s, 2H), 2.83(dt, J=13.3, 2.5 Hz, 2H), 4.19 (td, J=13.7, 4.3 Hz, 2H), 7.38 (dt,J=7.1, 0.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.61 (td, J=7.7, 1.2 Hz,1H), 7.70 (dt, J=7.4, 0.9 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ 28.38,37.52, 41.47, 41.58, 46.84, 79.73, 123.62, 123.87, 128.03, 135.09,135.61, 154.75, 162.02; GC-MS (EI) m/z 301.

1′-(tert-Butyloxycarbonyl)spiro(tetrahydro quinol-2-one)-4′-piperidine10 and 1′-(tert-butyloxycarbonyl)spiro(tetrahydroisoquinol-1-one)-4′-piperidine 9

To a cooled solution of 6 (10 g, 33 mmol) in dry benzene (40 mL),concentrated sulphuric acid was added with stirring. The reactionmixture was thereafter maintained at 40° C. under stirring followed bydropwise addition of a freshly prepared solution of hydrazoic acid (2.84g, 66 mmol) in benzene [A paste is prepared from 4.26 g of sodium azide,4.26 mL of water and 56.8 mL of benzene is added. The mixture is cooledto 0° C. and 1.18 mL of concentrated sulfuric acid is added dropwisewith control of temperature from 0-5° C. The organic layer (a solutionof hydrazoic acid in benzene) is separated, dried over sodium sulphateand used for the reaction. When the effervescence had ceased, thebenzene layer was carefully decanted off and the residue washed withbenzene (2×10 mL). Traces of benzene were removed under vacuo and theresidue dissolved in 70 mL of water followed by neutralization withliquor ammonia (10 mL). The reaction mixture was then treated with 7 gof solid sodium bicarbonate, di-tert-butyl pyrocarbonate (7.2 g) in 250mL of methylene chloride and stirred for 2 hours at ambient temperature.The organic layer was separated out and the aqueous part was washed withmethylene chloride (2×50 mL). The combined organic extract and washingswere washed with brine, dried (anhydrous Na2SO4), concentrated undervacuo to provide a foamy material which was chromatographed over silica(1:3 ethyl acetate-hexane followed by 1:1 ethyl acetate hexane) toprovide 1′-(tert-butyloxycarbonyl)spiro(tetrahydroquinol-2-one)-4′-piperidine 10 (6.7 g, 64%) as a creamish white solid,mp 198° C. IR (KBr) 3205, 3080, 2978, 1681, 1591, 1487, 1432, 1381,1252, 1174 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 1.67 (d, J=12.2Hz, 2H), 1.88 (br t, J=10.1 Hz, 2H), 2.70 (s, 2H), 3.08 (t, J=12.2 Hz,2H), 4.00 (br d, J=9.2 Hz, 2H), 6.83 (dd, J=7.8, 1.1 Hz, 1H), 7.06 (dt,J=7.6, 1.2 Hz, 1H), 7.20 (dt, J=7.6, 1.2 Hz, 1H), 7.29 (dd, J=7.3, 0.9Hz, 1H), 8.75 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 28.39, 33.69,35.32, 37.75, 39.31, 79.73, 116.38, 123.82, 124.00, 127.89, 131.25,136.24, 154.76, 170.67; GC-MS (EI) m/z 316.

1′-(tert-Butyloxycarbonyl)spiro(tetrahydroisoquinol-1-one)-4′-piperidine 9

This was compound was eluted with 1:1 ethyl acetate-hexane. (3.8 g, 36%)mp 182 0C; IR (KBr) 3337, 3232, 2867, 1692, 1679, 1635, 1603, 1415, 1165cm-1; 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.78 (m, 2H), 1.94 (br s,2H), 2.99 (t, J=12.9 Hz, 2H), 3.57 (br d, J=1.7 Hz, 2H), 4.01 (br d,J=15.6 Hz, 2H), 6.24 (br s, 1H), 7.38 (m, 2H), 7.53 (m, 1H), 8.10 (dd,J=7.9, 1.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 28.35, 29.59, 32.59,35.63, 44.79, 79.73, 122.99, 127.04, 127.83, 128.46, 132.83, 146.36,154.74; GC-MS (EI) m/z: (M−100).

6-Bromo-1′-(tert-butyloxycarbonyl)spiro(tetrahydroquinol-2-one)-4′-piperidine 11

A solution of 10 (10 g, 31.6 mmol) in dry acetonitrile (250 mL) wascooled to −10° C., and N-bromosuccinimide (5.62 g, 31.6 mmol) was addedportion wise with stirring. The reaction mixture was stirred for 1 h at−10 C, 2 h at 0° C. and finally at ambient temperature for 24 h. Thesolvent was removed and the residue dissolved in methylene chloride (500mL), organic extract washed with brine-water (1:1) (3×50 mL), dried(anhydrous Na2SO4), concentrated in vacuo to provide a creamish whitesolid which was chromatographed over silica (1:3 ethyl acetate-hexanefollowed by 1:1 ethyl-acetate hexane) to give6-bromo-1′-(tert-butyloxycarbonyl)spiro (tetrahydroquinol-2-one)-4′-piperidine 11 (11.8 g, 94%) as a white solid of mp 226°C. IR (KBr) 3178, 3083, 2923, 1686, 1586, 1491, 1432, 1380, 1255, 1171cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 1.65 (m, 2H), 1.85 (br t,2H), 2.69 (br s, 2H), 3.05 (br t, 2H), 4.02 (br s, 2H), 6.72 (d, J=8.4Hz, 1H), 7.32 (dd, J=8.4, 2.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 8.75 (s,1H); 13C NMR (100 MHz, CDCl3) δ 28.38, 33.56, 35.58, 37.31, 79.88,116.46, 117.93, 127.31, 130.76, 133.33, 135.39, 154.62, 170.58; GC-MS(EI) m/z (M−100) 294.

6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one 12

To a stirring solution of 11 (10 g, 25.3 mmol) in 750 mL of methanol,dry HCl was passed for 10 hrs and the stirring was continued forovernight. The reaction mixture was neutralized with liquor ammonia (75mL) under ice-cold condition. Methanol and excess ammonia were removedunder vacuo and the residue dissolved in methylene chloride (500 mL)followed by the addition of 25 mL of liquor ammonia to dissolve theremaining solid. The organic layer was separated out and the aqueouspart washed extracted with methylene chloride (3×150 mL), dried(anhydrous Na2SO4), concentrated under vacuo to provide6-bromo-spiro(tetrahydro quilon-2-one)-4′-piperidine 12 as a creamishwhite solid (7.0 g, 94%) of mp 218 0C. IR (KBr) 3434, 3318, 3180, 2823,1668, 1600, 1483, 1389 cm-1; 1H NMR (d6-DMSO, 400 MHz) δ 1.45 (d, J=12.7Hz, 2H), 1.71 (dt, J=12.3, 4.8 Hz, 2H); 2.57 (br s, 2H), 2.68-2.78 (m,4H), 6.83 (d, J=8.4 Hz, 1H), 7.33 (dd, J=8.4, 1.9 Hz, 1H), 7.41 (br d,J=1.9 Hz, 1H), 10.3 (br s, 1H); 1H NMR (D₂O exchange, d6-DMSO, 400 MHz)δ 1.43 (d, J=12.9 Hz, 2H), 1.71 (dt, J=12.2, 4.8 Hz, 2H), 2.55 (br s,2H), 2.65-2.76 (m, 4H), 6.82 (d, J=8.4 Hz, 1H), 7.29 (dd, J=8.4, 1.9 Hz,1H), 7.39 (br d, J=1.9 Hz, 1H); 13C NMR (100 MHz, d6-DMSO) δ 34.14,35.58, 37.34, 41.06, 114.28, 117.57, 126.75, 129.89, 134.74, 136.56,168.73; GC-MS (EI) m/z 294.

Example 26′-Bromo-1-(5H-[1,3]dioxolo[4,5-f]indol-6-ylcarbonyl)-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one

Amide coupling according to general procedure I:

-   -   Amine: 6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        (prepared herein above),    -   Acid: 5H-[1,3]Dioxolo[4,5-f]indole-6-carboxylic acid,

ES-MS m/e (%): 482.3 (M+H⁺).

Example 36′-Bromo-1-[(5-methoxy-1H-indol-2-yl)carbonyl]-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one

Amide coupling according to general procedure I:

-   -   Amine: 6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        (prepared herein above),    -   Acid: 5-Methoxy-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 468.4 (M+H⁺).

Example 46′-Bromo-1-[(5-fluoro-1H-indol-2-yl)carbonyl]-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one

Amide coupling according to general procedure I:

-   -   Amine: 6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        (prepared herein above),    -   Acid: 5-Fluoro-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 456.4 (M+H⁺).

Example 56′-Bromo-1-[(5-chloro-1-methyl-1H-indol-2-yl)carbonyl]-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one

Amide coupling according to general procedure I:

-   -   Amine: 6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        (prepared herein above),    -   Acid: 5-Chloro-1-methyl-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 488.3 (M+H⁺).

Example 6 {2-[(6′-Bromo-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinolin]-1-yl)carbonyl]-1H-indol-1-yl}acetonitrile

Amide coupling according to general procedure I:

-   -   Amine: 6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        (prepared herein above),    -   Acid: 1-Cyanomethyl-1H-indole-2-carboxylic acid (prepared herein        below),

ES-MS m/e (%): 477.4 (M+H⁺).

Cyanomethyl-1H-indole-2-carboxylic acid

To a solution of 1.0 eq. of 1-cyanomethyl-1H-indole-2-carboxylic acidethyl ester in a mixture of THF/H₂O ((9/1) was added LiOH.H₂O (1.0 eq.)and the reaction mixture stirred 6 h at RT, acidified to pH2 and thenpartially concentrated until precipitation of the crude product whichwas filtered off and washed with Et₂O and then dried to give the desiredproduct as a light yellow solid (70%).

ES-MS m/e (%): 199.0 (M−H⁺).

Example 7{2-[(6′-Bromo-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinolin]-1-yl)carbonyl]-5-chloro-1H-indol-1-yl}acetonitrile

Amide coupling according to general procedure I:

-   -   Amine: 6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        (prepared herein above),    -   Acid: 5-Chloro-1-cyanomethyl-1H-indole-2-carboxylic acid        (prepared herein below),

ES-MS m/e (%): 511.0 (M+H⁺).

5-Chloro-1-cyanomethyl-1H-indole-2-carboxylic acid

To a solution of 1.0 eq. of5-chloro-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (CAS126718-08-9; prepared according to Indian Journal of Chemistry, SectionB: Organic Chemistry Including Medicinal Chemistry (1989), 28B(12),1065-8) in a mixture of THF/H₂O ((9/1) was added LiOH.H₂O (1.0 eq.) andthe reaction mixture stirred 6 h at RT, acidified to pH 2 and thenpartially concentrated until precipitation of the crude product whichwas filtered off and washed with Et₂O and then dried to give the desiredproduct as a light yellow solid (84%).

Example 81-[(5-Chloro-1H-indol-2-yl)carbonyl]-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one

Amide coupling according to general procedure I:

-   -   Amine: 1′H-Spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        hydrochloride (prepared herein above),    -   Acid: 5-Chloro-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 394.4 (M+H⁺).

Example 96′-Bromo-1-[(5-chloro-1H-indol-2-yl)carbonyl]-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one

Amide coupling according to general procedure I:

-   -   Amine: 6′-Bromo-1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one        (prepared herein above),    -   Acid: 5-Chloro-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 470.3 (M−H⁺).

Example 101′-[(3-Methyl-1H-indol-2-yl)carbonyl]Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one

Amide coupling according to general procedure I:

-   -   Amine: Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (CAS        84060-09-3; described in Chemical & Pharmaceutical Bulletin        (1985), 33(3), 1129-39.),    -   Acid: 3-Methyl-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 374.4 (M−H⁺).

Example 111′-[(7-Methyl-1H-indol-2-yl)carbonyl]Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one

Amide coupling according to general procedure I:

-   -   Amine: Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (CAS        84060-09-3; described in Chemical & Pharmaceutical Bulletin        (1985), 33(3), 1129-39.),    -   Acid: 7-Methyl-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 376.4 (M+H⁺).

Example 121′-[(6-Chloro-1H-indol-2-yl)carbonyl]spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one

Amide coupling according to general procedure I:

-   -   Amine: Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (CAS        84060-09-3; described in Chemical & Pharmaceutical Bulletin        (1985), 33(3), 1129-39.),    -   Acid: 6-Chloro-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 396.4 (M+H⁺).

Example 131′-[(5-Methyl-1H-indol-2-yl)carbonyl]spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one

Amide coupling according to general procedure I:

-   -   Amine: Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (CAS        84060-09-3; described in Chemical & Pharmaceutical Bulletin        (1985), 33(3), 1129-39.),    -   Acid: 5-Methyl-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 376.4 (M+H⁺).

Example 141′-[(5-Chloro-1-methyl-1H-indol-2-yl)carbonyl]spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one

Amide coupling according to general procedure I:

-   -   Amine: Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (CAS        84060-09-3; described in Chemical & Pharmaceutical Bulletin        (1985), 33(3), 1129-39.),    -   Acid: 5-Chloro-1-methyl-1H-indole-2-carboxylic acid,

ES-MS m/e (%): 410.4 (M+H⁺).

Example 15{2-[(2-Oxo-1,2-dihydro-1′H-spiro[3,1-benzoxazine-4,4′-piperidin]-1′-yl)carbonyl]-1H-indol-1-yl}acetonitrile

Amide coupling according to general procedure I:

-   -   Amine: Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (CAS        84060-09-3; described in Chemical & Pharmaceutical Bulletin        (1985), 33(3), 1129-39.),    -   Acid: 1-Cyanomethyl-1H-indole-2-carboxylic acid (prepared herein        above),

ES-MS m/e (%): 401.4 (M+H⁺).

Example 16{5-Chloro-2-[(2-oxo-1,2-dihydro-1′H-spiro[3,1-benzoxazine-4,4′-piperidin]-1′-yl)carbonyl]-1H-indol-1-yl}acetonitrile

Amide coupling according to general procedure I:

-   -   Amine: Spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (CAS        84060-09-3; described in Chemical & Pharmaceutical Bulletin        (1985), 33(3), 1129-39.),    -   Acid: 5-Chloro-1-cyanomethyl-1H-indole-2-carboxylic acid        (prepared herein above),

ES-MS m/e (%): 435.4 (M+H⁺).

1. A compound of formula (Ib)

wherein R¹ is hydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH.or —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b); R¹ is hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), —(C₁₋₆-alkylene)-C(O)R^(f),benzyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; R³ is hydrogen, halo, orC₁₋₆-alkyl; R⁴ is hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, or —O—C₂₋₁₀-alkenyl; R⁵ is hydrogen,halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy; or R⁴ and R⁵ are bound together toform a ring with the benzo moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O—wherein n is 1 or 2; R⁶ is hydrogen, C₁₋₆-alkyl, optionally substitutedby CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h),-(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j), —O-benzyl, optionally substituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo, cyano, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, —(C₁₋₆-alkylene)-C(O)R^(f), phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, —(C₁₋₃-alkylene)-R^(m),wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4- to 6-memberedheterocycloalkyl or 3 to 6-membered cycloalkyl, each optionallysubstituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or R⁵ and R⁶ are boundtogether to form a ring with the benzo moiety, wherein —R⁵—R⁶ is—O—(CH₂)_(n)—C(O)—, —C(O)—(CH₂)_(n)—O—, or —O—(CH₂)_(n)—O— wherein n is1 or 2; R⁷ is hydrogen or C₁₋₆-alkyl; R⁸, R⁹, R¹⁰, and R¹¹ are eachindependently hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxyor halo-C₁₋₆alkoxy; R^(a), R^(b), R^(i) and R^(j) are each independentlyhydrogen, C₁₋₆-alkyl, —(C₁₋₆-alkylene)-NR^(k)R^(l); wherein R^(k) andR^(l) are each independently hydrogen or C₁₋₆-alkyl, or R^(a) and R^(b),or R^(i) and R^(j) together with the nitrogen to which they are boundform a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur;R^(c), R^(d), R^(g) and R^(h) are each independently hydrogen,C₁₋₆-alkyl, —C(O)R^(e), or —S(O)₂R^(e), wherein R^(e) is selected fromhydrogen, C₁₋₆-alkyl, and phenyl, optionally substituted by one or morehalo,  halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,  halo-C₁₋₆-alkoxy,nitro, or cyano, or R^(c) and R^(d), or R^(g) and R^(h) together withthe nitrogen to which they are bound form a five or six memberedheterocycle comprising one or two heteroatoms selected from the group ofnitrogen, oxygen and sulfur, or R^(c) and R^(d), or R^(g) and R^(h)together with the nitrogen to which they are bound formisoindole-1,3-dione; R^(f) is selected from hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy; and phenyl, optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano; or a pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1, wherein R¹ is hydrogen or C₁₋₆-alkyl, optionally substituted byCN or OH.
 3. The compound of claim 1, wherein R² is hydrogen,C₁₋₆-alkyl, C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), wherein R^(c) andR^(d) are each independently hydrogen, —C(O)R^(e), or —S(O)₂R^(e), wherein R^(e) is selected from  hydrogen,  C₁₋₆-alkyl, and  phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or R^(c) and R^(d)together with the nitrogen to which they are bound formisoindole-1,3-dione; -(C₁₋₆-alkylene)-C(O)R^(f), wherein R^(f) isselected from hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, and phenyl, optionallysubstituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; benzyl, optionallysubstituted by halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl, optionally substituted byhalo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro,or cyano.
 4. The compound of claim 1, wherein R² is hydrogen, orC₁₋₆-alkyl.
 5. The compound of claim 1, wherein R³ is hydrogen.
 6. Thecompound of claim 1, wherein R⁴ is hydrogen, halo, C₁₋₆-alkyl, orC₁₋₆-alkoxy.
 7. The compound of claim 1, wherein R⁶ is hydrogen,C₁₋₆-alkyl, optionally substituted by CN or OH,—(C₁₋₆-alkylene)-NR^(g)R^(h), wherein R^(g) and R^(h) are eachindependently selected from hydrogen and C₁₋₆-alkyl; or wherein R^(g)and R^(h) together with the nitrogen to which they are bound form a fiveor six membered heterocycle comprising one or two heteroatoms selectedfrom the group of nitrogen, oxygen and sulfur,—(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j), wherein R^(i) and R^(j) are eachindependently hydrogen, C₁₋₆-alkyl, —(C₁₋₆-alkylene)-NR^(k)R^(l), wherein R^(k) and R^(l) are each independently hydrogen or C₁₋₆-alkyl,or R^(i) and R^(j) together with the nitrogen to which they are boundform a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur,—O-benzyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo,cyano, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl,—(C₁₋₆-alkylene)-C(O)R^(f), R^(f) is selected from hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, and phenyl, optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano, phenyl, optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano, —(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to6-membered cycloalkyl, each optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano.
 8. The compound of claim 1, wherein R⁶ is hydrogen, C₁₋₆-alkyl,optionally substituted by CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h),wherein R^(g) and R^(h) are each independently selected from hydrogenand C₁₋₆-alkyl; or wherein R^(g) and R^(h) together with the nitrogen towhich they are bound form a five or six membered heterocycle comprisingone or two heteroatoms selected from the group of nitrogen, oxygen andsulfur, —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j), wherein R^(i) and R^(j) areeach independently hydrogen, C₁₋₆-alkyl, —(C₁₋₆-alkylene)-NR^(k)R^(l), wherein R^(k) and R^(l) are each independently hydrogen or C₁₋₆-alkyl,or R^(i) and R^(j) together with the nitrogen to which they are boundform a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur,—O-benzyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo,cyano, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl,-(C₁₋₆-alkylene)-C(O)R^(f), R^(f) is selected from hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, and phenyl, optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano, phenyl, optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano, —(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to6-membered cycloalkyl, each optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano.
 9. The compound of claim 1, wherein R⁶ is hydrogen or C₁₋₆-alkyl,optionally substituted by CN or OH.
 10. The compound of claim 1 whereinR⁷ is hydrogen.
 11. The compound of claim 1, wherein R⁸, R⁹, R¹⁰ and R¹¹are independently hydrogen or halo.
 12. The compound of claim 1, whereinR⁸, R⁹, R¹⁰ and R¹¹ are each hydrogen.
 13. The compound of claim 1,wherein R⁸, R⁹, and R¹¹ are each hydrogen and R¹⁰ is bromine.
 14. Thecompound of claim 1, wherein R⁹ is fluorine and R⁸, R¹⁰ and R¹¹ are eachhydrogen.
 15. The compound of claim 1, wherein R⁸, R⁹, R¹⁰ and R¹¹ areeach independently hydrogen or methyl.
 16. The compound of claim 1,wherein R⁸, R⁹, and R¹⁰ are hydrogen and R¹ is methyl.
 17. The compoundof claim 1, which is{2-[(6′-bromo-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinolin]-1-yl)carbonyl]-5-chloro-1H-indol-1-yl}acetonitrile.18. The compound of claim 1, wherein none of R¹ to R⁶ are hydrogen. 19.The compound of claim 1, wherein none of R¹ to R¹¹ are hydrogen.
 20. Thecompound of claim 1, wherein R^(a) and R^(b), R^(c) and R^(d), R^(i) andR^(j), or R^(g) and R^(h) together with the nitrogen to which they arebound form piperazine, 4-(C₁₋₆-alkyl)-piperazine, 4-methylpiperazine,morpholine, piperidine, or pyrrolidine.
 21. The compound of claim 1,wherein R^(m) is a 5- to 6-membered heteroaryl selected from the groupconsisting of pyridine, pyrimidine, pyrazine, pyridazine, imidazole,pyrazole, oxazole, and isoxazole.
 22. The compound of claim 1, whereinR^(m) is a 4- to 6-membered heterocycloalkyl group selected from thegroup consisting of pyrrolidine, oxethane, tetrahydropyrane, piperidine,morpholine, and piperazine.
 23. The compound of claim 1, wherein R¹ ishydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH; R² is hydrogenor C₁₋₆-alkyl; R³ is hydrogen; R⁴ is hydrogen, halo, or C₁₋₆-alkyl; R⁵is hydrogen, or halo; R⁶ is hydrogen or C₁₋₆-alkyl optionallysubstituted by CN or OH; R⁷ is hydrogen; and R⁸, R⁹, R¹⁰, and R¹¹ areeach hydrogen.
 24. A pharmaceutical composition comprising atherapeutically effective mount of a compound of formula (Ib)

wherein R¹ is hydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH.or -(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b); R² is hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), -(C₁₋₆-alkylene)-C(O)R^(f),benzyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; R³ is hydrogen, halo, orC₁₋₆-alkyl; R⁴ is hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, or —O—C₂₋₁₀-alkenyl; R⁵ is hydrogen,halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy; or R⁴ and R⁵ are bound together toform a ring with the benzo moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O—wherein n is 1 or 2; R⁶ is hydrogen, C₁₋₆-alkyl, optionally substitutedby CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h),—(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j), —O-benzyl, optionally substituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo, cyano, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, —(C₁₋₆-alkylene)-C(O)R^(f), phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, —(C₁₋₃-alkylene)-R^(m),wherein R^(m) is phenyl, a 5- to 6-membered heteroaryl, 4- to 6-memberedheterocycloalkyl or 3 to 6-membered cycloalkyl, each optionallysubstituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or R⁵ and R⁶ are boundtogether to form a ring with the benzo moiety, wherein —R⁵—R⁶ is—O—(CH₂)_(n)—C(O)—, —C(O)—(CH₂)_(n)—O—, or —O—(CH₂)_(n)—O— wherein n is1 or 2; R⁷ is hydrogen or C₁₋₆-alkyl; R⁸, R⁹, R¹⁰, and R¹¹ are eachindependently hydrogen, halo, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxyor halo-C₁₋₆alkoxy; R^(a), R^(b), R^(i) and R^(j) are each independentlyhydrogen, C₁₋₆-alkyl, —(C₁₋₆-alkylene)-NR^(k)R^(l); wherein R^(k) andR^(l) are each independently hydrogen or C₁₋₆-alkyl, or R^(a) and R^(b),or R^(i) and R^(j) together with the nitrogen to which they are boundform a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur;R^(c), R^(d), R^(g) and R^(h) are each independently hydrogen,C₁₋₆-alkyl, —C(O)R^(e), or —S(O)₂R^(e), wherein R^(e) is selected fromhydrogen, C₁₋₆-alkyl, and phenyl, optionally substituted by one or morehalo,  halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,  halo-C₁₋₆-alkoxy,nitro, or cyano, or R^(c) and R^(d), or R^(g) and R^(h) together withthe nitrogen to which they are bound form a five or six memberedheterocycle comprising one or two heteroatoms selected from the group ofnitrogen, oxygen and sulfur, or R^(c) and R^(d), or R^(g) and R^(h)together with the nitrogen to which they are bound formisoindole-1,3-dione; R^(f) is selected from hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy; and phenyl, optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano; or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.